Tuberculosis: what we don't know can, and does, hurt us

Abstract

Mycobacterium tuberculosis has a penetrance of its host population that would be the envy of most human pathogens. About one-third of the human population would have a positive skin test for the infection and is thus thought to harbor the bacterium. Globally, 22 "high-burden" countries account for more than 80% of the active tuberculosis cases in the world, which shows the inequitable distribution of the disease. There is no effective vaccine against infection, and current drug therapies are fraught with problems, predominantly because of the protracted nature of the treatment and the increasing occurrence of drug resistance. Here we focus on the biology of the host-pathogen interaction and discuss new and evolving strategies for intervention.

Figure 1. The life cycle of Mycobacterium tuberculosis

The infection is initiated when Mtb, present in exhaled droplets or nuclei, are inhaled and phagocytosed by resident alveolar macrophages. The resulting pro-inflammatory response triggers the infected cells to invade the subtending epithelium. This response also leads to the recruitment of monocytes from the circulation and extensive neovascularization of the infection site. The macrophages in the granulomas differentiate to form epithelioid cells, multi-nucleate giant cells and foam cells filled with lipid droplets. The granuloma can become further stratified by the formation of a fibrous cuff of extracellular matrix material that is laid down outside the macrophage layer. Lymphocytes appear to be restricted primarily to this peripheral area. Many of the granulomas persist in this balanced state, but progression towards disease is characterized by the loss of vascularization, the increased necrosis and the accumulation of caseum in the granuloma center. Ultimately, infectious bacilli are released into the airways when the granuloma cavitates and collapses into the lungs.

Figure 2. The Bacterial Load in Naïve and Immune Hosts

The course of Mtb infection in naïve and immune hosts follows a reproducible pattern in the mouse model. Following infection the bacteria replicate exponentially for a period of time until the host develops an acquired immune response, which limits bacterial replication. At this time the infection transitions to a state of persistence or chronicity where the bacterial load is sustained at a relatively constant level. Transition into this persistent state occurs earlier in a vaccinated host, or a host that has been infected and treated chemotherapeutically. In mice vaccinated with BCG this transition occurs with a bacterial load that is approximately 10 fold fewer than naïve host. The transition into persistence is marked by the development of a granuloma.

Figure 3. Imaging disease progression in humans

¹⁸F-FDG-PET/CT scan from a patient with pulmonary TB at the time when therapy was initiated (left panels) and 2 months after treatment has begun (right panels). Below are two matched axial CT slices from the area indicated by the plane on the left taken from the same scans. FDG is primarily a marker of increased tissue metabolism such as inflammation while the CT shows the structural abnormalities within this patient's lungs. Both sets of images illustrate the wide range of lesion types occupied by Mtb during infection that show differential kinetics of response to chemotherapy.